Periodontal disease (Pyorrhea) involves the inflammation and degeneration of tissues that surround and support mammalian teeth. These include the gingiva, alveolar bone, periodontal ligament, and cementum. Periodontitis or the loss of supporting bone is the latest stage of this progressive disorder and is the major cause of tooth loss in adults. Juveniles also experience a form of periodontitis which results in alveolar bone loss and subsequent loss of teeth. Identified causal factors for this disease include poor hygiene which leads to buildup of bacterial plaque; malocclusion, tartar buildup, food impaction, and faulty dental restorations. The rate of osseous bone loss (resorption) depends upon the severity of the above conditions or causative factors. Symptoms of periodontitis include deepening of the gingival pockets between the gingivae and the teeth; loss of attachment of the gums to the teeth; and bone loss. Microbes proliferate in the recessed areas and accelerate disease progression. Periodontal surgery remains the primary corrective measure of this disease. Periodontal surgery (scaling and planing), however, may induce or, at a minimum, is associated with periodontal bone loss.
Antibiotics, astringent agents, and mouthwashes are not effective for long-term treatment of periodontal disease. Home care that includes brushing, rinsing, and flossing coupled with dental curettage and polishing help deter the disease. Other preventative treatments include hydrogen peroxide mouth rinses (3 percent H.sub.2 O.sub.2 in warm water). Carbamide peroxide (Urea hydrogen peroxide, CH.sub.6 N.sub.2 O.sub.3) is also used in the local treatment of minor infections and inflammation caused by periodontitis. Penicillin (1000-1500 milligrams daily) or erythromycin may be used if severe oral signs or symptoms are present.
An additional approach to the treatment of periodontal disease includes the use of non-steroidal anti-inflammatory agents to hinder disease progression. It is known according to U.S. Pat. No. 4,677,132 that the analgesic and anti-inflammatory agent Etodolac may also inhibit bone resorption and bone loss associated with periodontal disease. Etodolac is a substituted pyrano [3,4 b] indole derivative. U.S. Pat. No. 4,440,779 describes the use of novel tricyclic analgesic and anti-inflammatory agents useful in the treatment of fever, pain and inflammatory conditions associated with arthritis, spondylitis, gout, dysmennohrea, upper respiratory disorders, and periodontal diseases.
The use of a number of bisphosphonic acid derivatives in the treatment of a broad range of calcium metabolism disorders including periodontitis is known. Eur. Pat. App. No. -320-455-A discloses the use of N-aralkyl-amino-1-hydroxyalkane-1,1-diphosphonic derivatives as useful in the treatment of inflammatory/degenerative joint diseases, osteoporosis, periodontitis, and hyperthyroidism. Eur. Pat. App. No. -317-505-A discloses the use of 1-hydroxy-alkane-1,1-diphosphonic acid derivatives with azabicycloalkyl substitutions as useful for treating calcium metabolism disorders. The specific diseases mentioned include osteoporosis, hyperparathyroidism periodontitis, arthritis, neuritis, bursitis, tendinitis, fibrodysplasia, arteriosclerosis, Paget's disease, and osteodystrophia fibrosa. Australian Pat. App. No. 8781-453-A discloses the use of 2-heteroarylethane-1,1-diphosphonic acids as useful in the treatment of calcium metabolism disorders. Eur. Pat. App. No. -274-346-A discloses the use of 1-Azaheterocycloamino-methyl-1,1-diphosphonic acid derivatives to treat the same disorders. Eur. Pat. App. No. -272-208-A discloses the use of Azacycloalkyl-substituted 1-hydroxyalkane-1,1-diphosphonic acid compounds as useful also. Eur. Pat. App. No. -320-118-A discloses the use of phosphorus containing peptides useful as collagenase inhibitors and refers to periodontal disease.
As suggested above, it is known that bone resorption may be effectively treated with a variety of bisphosphonic acid derivatives. U.S. Pat. No. 4,621,077 ('077) describes the use of 4-amino-1-hydroxybutylidene-1,1 bisphosphonic acid ("ABP") in the treatment of bone loss that occurs in various bone diseases. The '077 patent teaches that the claimed bisphosphonic acid and its salt have inhibitory activity on bone reabsorption. Other phosphonate derivatives have been used to treat bone resorption. U.S. Pat. No. 5,002,937 describes novel diphosphonic acid compounds useful for treating calcium metabolism disorders. The '937 patent claims aminoalkane 1,1 diphosphonic acids in which the alkyl chain is interrupted by an oxygen atom (an ether link). European Patent Application No. 0 449 405 A2 broadly discloses the use of bisphosphonic acids for the treatment of calcium metabolism disorders. In particular, this European Application discloses the use of the calcium salt of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid in the treatment of a multitude of bone diseases. U.S. Pat. Nos. 4,990,503 and 4,973,576 describe novel heterocyclic bisphosphonic acid derivatives that are potent bone resorption inhibitors. The art also suggests that the effects of bisphosphonates are variable and can produce opposite effects with different bisphosphonates or produce different biological responses at different concentrations with identical bisphosphonates. Fleish, H. Clin. Ortop., 217, 72-78 (1987).
U.S. Pat. No. 3,962,432 issued on Jun. 8, 1976 describes the use of 3-amino-1-hydroxypropane-1,1-disphosphonic acid in tarter control. U.S. Pat. No. 4,446,052 discloses the use of a calcium salt of 1-hydroxy-3-aminopropane-1,1-disphosphonic acid derivative to treat dental calculus and plaque. U.S. Pat. No. 4,877,603 teaches the use of geminal diphsophonate polymers in the treatment of plaque. Various other patents disclose the use of phosphonates as antigingivitis agents. These include U.S. Pat. Nos. 3,429,963; 4,102,993; 4,042,679; 4,100,270; 4,098,880; 4,123,512; and 4,138,477. Periodontal destruction in rice rats may be inhibited by bisphosphonates. Fleish, H. Clin. Ortop., 217, 72-78 (1987).
U.S. Pat. Nos. 4,711,880 and 4,639,338 disclose the preparation of 3-amino-1-hydroxypropane-1,1-diphosphonate pentahydrate.
The patent literature also describes the use of agents to induce new bone apposition in vivo. U.S. Pat. No. 4,816,437 discloses an alpha.sub.2 HS-Glycoprotein that induces bone apposition at a particular defective site. Bisphosphonates have been used to alter mineralization of the teeth. For example, the deposition of mineral crystallites in newly formed dentin is inhibited by 1-hydroxyethylidene-1,1-bisphosphonate. Beertsen, W., Neihof A., Everts, V. American J. Anat, 174, 83-103 (1985). These compounds may also affect collagen fibrilogenesis. Larsson, A. Calcif. Tissue Res., 16, 109-127 (1974); Ogawa Y, Adachi Y, Hong S, yagi, T. Calcif. Tissue Internat., 44, 46-60 (1989). Ultrastructural effects of disphosphonates on dental enamel has been studied as well. Simmelink, J. W., Adv. Dental Res. 1, 356-365 (1987). Prior to the instant invention, the art has not disclosed the use of a safe and highly effective bisphosphonate derivative to treat alveolar bone loss associated with periodontal disease in higher mammals. Treatment of this disease with anti-inflammatory agents and antibiotics only partially arrests progression of periodontitis.
Periodontal disease and periodontitis, as distinguished from other bone loss or calcium metabolism disorders, and the accompanying alvelolar bone loss, is caused by aggressive bacterial or microbial buildup. It is generally assumed that plaque microorganisms and the products they produce are primarily responsible for periodontal disease. Riviere et al., Infection and Immunity, 59(10), 3377-3380 (1991). Spirochetes (non-flagellated, spiral bacteria) are major microbial components of dental plaque. Several other bacterial types may also be involved in periodontal disease progression including Bacteroides melaninogenicus (Prevotella melaninogenica), Prevotella denticola, Prevotella loescheii, Bacteroides macacae, Porphyromonas gingivalis, Prevotella intermedia, Actinobacillus actinomycetemcomitans, Eikenella corrodens, and Wolinella recta. Ebersole et al., Infection and Immunity, 59(10), 3351-3359 (1991). Active immunization with two of the well-established members of peridontpathic microbiota, P. gingivalis and P. intermedia as a possible alternative treatment has been found to induce a significant immune response but, the resultant antibodies did not prevent alveolar bone loss. Ebersole et al., Infection and Immunity, 59(10), 3351-3359 (1991). Periodontal disease is a universal disease which may affect over 95 percent of the world's population. S. Cripps, "Periodontal Disease: Recognition, Interception and Prevention", Quintessence Publishing Co. (1984). There is, therefore, a significant need for an effective treatment of alveolar bone loss associated with advanced peridontitis. There is an additional need to have an adequate adjunct therapy to prevent or treat bone loss associated with periodontal surgery. The instant claimed invention may advantageously be used as an adjunct therapy in conjunction with or after periodontal surgery to treat alveolar bone loss. One objective of the present invention is to combine a pharmaceutically effective amount of ABP or a pharmaceutically acceptable salt such as alendronate with known anti-inflammatory agents (for example, the analgesic and anti-inflammatory agent described in U.S. Pat. No. 4,677,132 or that described in U.S. Pat. No. 4,440,779) or known anti-microbial agents (for example, penicillin or erythromycin) to treat the overall progression of periodontal disease. Alternatively, ABP or its pharmaceutically acceptable salt such as alendronate can be used separately and/or concurrently with anti-microbial and/or anti-inflammatory agents to prevent, arrest, and treat periodontal disease.